During the reporting year, the NCGC worked with over 300 researchers worldwide to advise them on assay design and development, chemistry research, informatics research, technology development projects, and to run high-throughput screens and chemically optimize small molecule leads. In collaboration with the Molecular Libraries Probe Production Centers Network (MLPCN), the U.S. Environmental Protection Agency, the National Toxicology Program, NIEHS, FDA, NCI, numerous rare disease foundations, and other intramural and extramural laboratories, the NCGC performed over 60 high-throughput screens on molecular targets and cellular phenotypes important for virtually every area of biology and disease. The NCGC also continued its work in the field of siRNA, completing 2 full-scale siRNA screening campaigns including follow-up, 3 primary screens (7,000 genes), and 6 pilot screens (1,000 genes). 20 new chemical probes of diverse biologies were discovered, and NCGC scientists published 43 publications during FY10. The NCGC obtained 3 patents during this reporting period. Also during the reporting period, the NCGC deposited 195 BioAssays, 38 Summary AIDs, 7,734,000 concentration response curves, and a total of 46,404,000 data points into PubChem. NCGC continued to apply its chemistry expertise to optimizing probes;28 chemistry projects were implemented during the year. Under leadership from NCGC, along with the U.S. Environmental Protection Agency and the National Toxicology Program of NIEHS, the Toxicology in the 21st Century project (Tox21) continued to flourish. Tox21 is an initiative designed to predict the toxicity of chemicals on human health and the environment. This is accomplished by developing in vitro assays for more predictive, mechanistically-based methods than those used with current animal testing. In July 2010, the FDA joined the collaboration;the FDA brings human toxicity data into the project, along with other expertise, to improve upon current chemical testing methods. In the current reporting year, NCGC completed 20 full Tox21 screens and 152 smaller-scale screens on specific, varied cell lines. Given the NCGC's continual efficiency improvement program, we were able to increase the throughput of existing robotic screening, informatics, and chemistry systems by improvements in applications, software, and utilization scheduling, driven by both the project teams and Project Management. The NCGC maintained its existing robotic technology and Bio Safety Levels 1, 2, and 3 facilities during the reporting period, in addition to adding a new robotic system dedicated to RNAi screening. The NCGC's Outreach program continued its extraordinary record of productivity during the reporting period. NCGC staff advised 245 outside investigators on assay design and assay development, and assisted over 40 investigators with chemistry, informatics, and technology development inquiries. NCGC scientists gave 104 invited presentations throughout the U.S., Europe, and Asia during the period. NCGC outreach resulted in the submission of over 60 assay development and screening applications for MLPCN programs. The NCGC website (ncgc.nih.gov) was maintained and is currently being completely redesigned, to be incorporated into an overall NCGC/TRND site. The Assay Guidance manual on the NCGC website has continued to evolve and has become a central resource for investigators interested in MLPCN science. To allow scientists across the world to share information on the topic, an Assay Wiki feature was designed and implemented during FY10. During the reporting period, the manual received 608,147 hits, with 48,437 unique visitors. 47% of these visitors originated from outside the US, from a total of 125 countries. The number of hits indicates that many Assay Guidance Manual readers are repeat visitors who find the resource useful to revisit on a frequent basis. During the year, the NCGC also maintained its status as an active member of the NCI's Chemical Biology Consortium. In addition, NCGC successfully competed for NIH funds dedicated to an induced pluripotent stem cell project, on which work has commenced. NCGC continued to work on its NIH Directors Challenge Award for malaria research. Finally, NCGCs work on its two IATAP grants continued and was submitted for renewal;the two IATAP awards include a program to modify non-nucleoside reverse transcriptase inhibitors to extend their potency range into newly characterized RT mutants, and a program to modify the natural product manicol to inhibit the RNAse domain of HIV RT.